JPWO2020002270A5 - - Google Patents
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- Publication number
- JPWO2020002270A5 JPWO2020002270A5 JP2020572638A JP2020572638A JPWO2020002270A5 JP WO2020002270 A5 JPWO2020002270 A5 JP WO2020002270A5 JP 2020572638 A JP2020572638 A JP 2020572638A JP 2020572638 A JP2020572638 A JP 2020572638A JP WO2020002270 A5 JPWO2020002270 A5 JP WO2020002270A5
- Authority
- JP
- Japan
- Prior art keywords
- methoxy
- ethyl
- methoxyazetidine
- pyridine
- cyclopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 1-fluoro-propa-2- Il Chemical group 0.000 claims description 463
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 274
- 150000001875 compounds Chemical class 0.000 claims description 219
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 211
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 207
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 198
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 186
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 110
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 101
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 94
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 65
- 238000000034 method Methods 0.000 claims description 53
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 45
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 claims description 44
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 39
- 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 claims description 38
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 38
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 33
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 32
- AVPAYFOQPGPSCC-UHFFFAOYSA-N 3-methoxyazetidine Chemical compound COC1CNC1 AVPAYFOQPGPSCC-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 20
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 206010061218 Inflammation Diseases 0.000 claims description 18
- 230000004054 inflammatory process Effects 0.000 claims description 18
- 208000017169 kidney disease Diseases 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 206010063837 Reperfusion injury Diseases 0.000 claims description 15
- 206010016654 Fibrosis Diseases 0.000 claims description 14
- 230000004761 fibrosis Effects 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 230000001052 transient effect Effects 0.000 claims description 11
- 201000001320 Atherosclerosis Diseases 0.000 claims description 10
- 206010019695 Hepatic neoplasm Diseases 0.000 claims description 10
- HZLCNNLHONIXGK-UHFFFAOYSA-N N-(3-methoxyazetidin-1-yl)pyridine-2-carboxamide Chemical compound N1=C(C=CC=C1)C(=O)NN1CC(C1)OC HZLCNNLHONIXGK-UHFFFAOYSA-N 0.000 claims description 10
- 208000002193 Pain Diseases 0.000 claims description 10
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 10
- 210000000988 bone and bone Anatomy 0.000 claims description 10
- 230000001684 chronic effect Effects 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 208000012947 ischemia reperfusion injury Diseases 0.000 claims description 10
- 230000000302 ischemic effect Effects 0.000 claims description 10
- 208000014018 liver neoplasm Diseases 0.000 claims description 10
- 208000010125 myocardial infarction Diseases 0.000 claims description 10
- 230000009885 systemic effect Effects 0.000 claims description 10
- 208000007788 Acute Liver Failure Diseases 0.000 claims description 9
- 206010000804 Acute hepatic failure Diseases 0.000 claims description 9
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 9
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 9
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 9
- 208000010412 Glaucoma Diseases 0.000 claims description 9
- 206010019280 Heart failures Diseases 0.000 claims description 9
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 9
- 208000021908 Myocardial disease Diseases 0.000 claims description 9
- 206010037660 Pyrexia Diseases 0.000 claims description 9
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 9
- 206010052779 Transplant rejections Diseases 0.000 claims description 9
- 230000001154 acute effect Effects 0.000 claims description 9
- 231100000836 acute liver failure Toxicity 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 230000002490 cerebral effect Effects 0.000 claims description 9
- 230000007850 degeneration Effects 0.000 claims description 9
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 9
- 230000001434 glomerular Effects 0.000 claims description 9
- 208000031225 myocardial ischemia Diseases 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 9
- 231100000241 scar Toxicity 0.000 claims description 9
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 8
- 206010023421 Kidney fibrosis Diseases 0.000 claims description 8
- 230000008719 thickening Effects 0.000 claims description 8
- 208000002260 Keloid Diseases 0.000 claims description 7
- 206010056677 Nerve degeneration Diseases 0.000 claims description 7
- 150000003857 carboxamides Chemical class 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 210000001117 keloid Anatomy 0.000 claims description 7
- 230000001568 sexual effect Effects 0.000 claims description 7
- 206010010904 Convulsion Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000006456 halo alkyl cycloalkyl group Chemical group 0.000 claims description 5
- 125000003566 oxetanyl group Chemical group 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 206010023330 Keloid scar Diseases 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 claims description 3
- 239000007822 coupling agent Substances 0.000 claims description 3
- 125000005817 fluorobutyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000006419 fluorocyclopropyl group Chemical group 0.000 claims description 3
- 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- YZWQRUIPOGSGIZ-ZDUSSCGKSA-N C[C@@H](CO)N(CC=C1)C(OCC2(CF)COC2)=C1N(C1)CC1OC Chemical compound C[C@@H](CO)N(CC=C1)C(OCC2(CF)COC2)=C1N(C1)CC1OC YZWQRUIPOGSGIZ-ZDUSSCGKSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 189
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 138
- 239000000203 mixture Substances 0.000 description 93
- 235000019439 ethyl acetate Nutrition 0.000 description 86
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 78
- 239000012071 phase Substances 0.000 description 66
- 239000000243 solution Substances 0.000 description 65
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 62
- 239000011541 reaction mixture Substances 0.000 description 51
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 47
- 239000012044 organic layer Substances 0.000 description 45
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 42
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000012267 brine Substances 0.000 description 33
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
- 239000012230 colorless oil Substances 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000012043 crude product Substances 0.000 description 29
- 125000006239 protecting group Chemical group 0.000 description 25
- 239000011734 sodium Substances 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000013058 crude material Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 235000019198 oils Nutrition 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 238000000746 purification Methods 0.000 description 14
- 229910004298 SiO 2 Inorganic materials 0.000 description 13
- 229910000175 cerite Inorganic materials 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- SEBJRHGSFJEWFZ-UHFFFAOYSA-N 5-bromo-6-chloropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Br)C(Cl)=N1 SEBJRHGSFJEWFZ-UHFFFAOYSA-N 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 239000012317 TBTU Substances 0.000 description 10
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- GQERJQAZXHCDQN-UHFFFAOYSA-N ethyl 2-amino-2-ethylbutanoate;hydrochloride Chemical compound Cl.CCOC(=O)C(N)(CC)CC GQERJQAZXHCDQN-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 9
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 9
- 102100036214 Cannabinoid receptor 2 Human genes 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
- 101710187022 Cannabinoid receptor 2 Proteins 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- XGVXNTVBGYLJIR-UHFFFAOYSA-N fluoroiodomethane Chemical compound FCI XGVXNTVBGYLJIR-UHFFFAOYSA-N 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- KSXGQRBTBLQJEF-UHFFFAOYSA-N 3-methoxyazetidine;hydrochloride Chemical compound Cl.COC1CNC1 KSXGQRBTBLQJEF-UHFFFAOYSA-N 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 208000028867 ischemia Diseases 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000004296 chiral HPLC Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000010410 reperfusion Effects 0.000 description 5
- 230000000717 retained effect Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- SMDYQFCZGKZHDG-UHFFFAOYSA-N 1-fluoro-1-iodoethane Chemical compound CC(F)I SMDYQFCZGKZHDG-UHFFFAOYSA-N 0.000 description 4
- URBUZQPPQLQHBZ-UHFFFAOYSA-N 1-fluoro-3-iodopropane Chemical compound FCCCI URBUZQPPQLQHBZ-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- PXBBQQKQMZDHKX-UHFFFAOYSA-N 5-(3-methoxyazetidin-1-yl)-6-(oxetan-3-ylmethoxy)pyridine-2-carboxylic acid Chemical compound COC1CN(C1)C=1C=CC(=NC=1OCC1COC1)C(=O)O PXBBQQKQMZDHKX-UHFFFAOYSA-N 0.000 description 4
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- 101000875075 Homo sapiens Cannabinoid receptor 2 Proteins 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
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| JP7456948B2 (ja) | 2018-06-27 | 2024-03-27 | エフ． ホフマン－ラ ロシュ アーゲー | 放射性標識カンナビノイド受容体２リガンド |
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| US9321727B2 (en) * | 2011-06-10 | 2016-04-26 | Hoffmann-La Roche Inc. | Pyridine derivatives as agonists of the CB2 receptor |
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| UA114657C2 (uk) | 2012-12-07 | 2017-07-10 | Ф. Хоффманн-Ля Рош Аг | Піридин-2-аміди, придатні як агоністи канабіноїдного рецептора 2 |
| LT2928868T (lt) | 2012-12-07 | 2017-10-25 | F. Hoffmann-La Roche Ag | Piridin-2-amidai, tinkami naudoti kaip cb2 agonistai |
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| JP6322646B2 (ja) | 2012-12-07 | 2018-05-09 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Ｃｂ２受容体アゴニストとしての新規ピラジン誘導体 |
| ES2661737T3 (es) | 2013-03-26 | 2018-04-03 | F. Hoffmann-La Roche Ag | Derivados de piridina novedosos |
| JP6654574B2 (ja) | 2014-04-04 | 2020-02-26 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Ｃｂ２アゴニストとして有用なピリジン−２−アミド |
| PE20161407A1 (es) | 2014-04-04 | 2016-12-28 | Hoffmann La Roche | Piridina 5,6 disustituida -2-carboxamidas como agonistas del receptor canabinoide |
| MX2018006802A (es) | 2015-12-09 | 2018-09-05 | Hoffmann La Roche | Derivados de fenilo como agonistas del receptor de canabinoides 2. |
| CN110753690B (zh) | 2017-06-20 | 2023-12-05 | 豪夫迈·罗氏有限公司 | 吡啶衍生物 |
| PE20210368A1 (es) | 2018-06-27 | 2021-02-26 | Eth Zuerich | Nuevos compuestos de piridina y pirazina como inhibidores del receptor cannabinoide 2 |
| CN112119068A (zh) | 2018-06-27 | 2020-12-22 | 豪夫迈·罗氏有限公司 | 作为大麻素受体2的抑制剂的新型氮杂环丁烷-取代的吡啶和吡嗪化合物 |
| JP7456948B2 (ja) | 2018-06-27 | 2024-03-27 | エフ． ホフマン－ラ ロシュ アーゲー | 放射性標識カンナビノイド受容体２リガンド |
| TWI687701B (zh) | 2018-12-05 | 2020-03-11 | 宏碁股份有限公司 | 判斷電量狀態的方法及其電子裝置 |
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- 2019-06-25 CN CN201980029322.XA patent/CN112074513B/zh active Active
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2020
- 2020-12-17 US US17/125,647 patent/US11655243B2/en active Active
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